Tickle Ian, Sharff Andrew, Vinkovic Mladen, Yon Jeff, Jhoti Harren
Astex Technology Ltd., 436 Science Park, Milton Road, Cambridge, UK.
Chem Soc Rev. 2004 Oct 20;33(8):558-65. doi: 10.1039/b314510g. Epub 2004 Sep 20.
Single crystal X-ray diffraction is the technique of choice for studying the interactions of small organic molecules with proteins by determining their three-dimensional structures; however the requirement for highly purified protein and lack of process automation have traditionally limited its use in this field. Despite these shortcomings, the use of crystal structures of therapeutically relevant drug targets in pharmaceutical research has increased significantly over the last decade. The application of structure-based drug design has resulted in several marketed drugs and is now an established discipline in most pharmaceutical companies. Furthermore, the recently published full genome sequences of Homo sapiens and a number of micro-organisms have provided a plethora of new potential drug targets that could be utilised in structure-based drug design programs. In order to take maximum advantage of this explosion of information, techniques have been developed to automate and speed up the various procedures required to obtain protein crystals of suitable quality, to collect and process the raw X-ray diffraction data into usable structural information, and to use three-dimensional protein structure as a basis for drug discovery and lead optimisation. This tutorial review covers the various technologies involved in the process pipeline for high-throughput protein crystallography as it is currently being applied to drug discovery. It is aimed at synthetic and computational chemists, as well as structural biologists, in both academia and industry, who are interested in structure-based drug design.
单晶X射线衍射是通过确定小分子有机化合物与蛋白质的三维结构来研究它们之间相互作用的首选技术；然而，对高纯度蛋白质的要求以及缺乏过程自动化，传统上限制了其在该领域的应用。尽管存在这些缺点，但在过去十年中，治疗相关药物靶点的晶体结构在药物研究中的应用显著增加。基于结构的药物设计的应用已产生了几种上市药物，并且现在在大多数制药公司中已成为一门成熟的学科。此外，最近公布的人类和一些微生物的全基因组序列提供了大量新的潜在药物靶点，可用于基于结构的药物设计项目。为了充分利用这一信息爆炸，已开发出各种技术来自动化和加速获得合适质量蛋白质晶体、将原始X射线衍射数据收集和处理成可用结构信息以及将三维蛋白质结构用作药物发现和先导优化基础所需的各种程序。本教程综述涵盖了高通量蛋白质晶体学流程中涉及的各种技术，因为它目前正应用于药物发现。它面向学术界和工业界对基于结构的药物设计感兴趣的合成化学家和计算化学家以及结构生物学家。
